A single feeding of potent protein immunogen, such as ovalbumin, can induced substantial, carrier-specific unresponsiveness in high- or low-responder strains of mice. Parenteral injections of this antigen, in quantities similar to those absorbed into the blood after feeding, tend to be immunogenic rather than tolerogenic. Completed and current research have identified several major factors determining the occurrence and degree of orally induced tolerance, and characterized both cellular and functional properties of the tolerant state. Other objectives are to pursue the evaluation of immunologic mechanisms of this tolerance, with emphasis on the critical events associated with its induction, taking advantage of the highly effective tolerance induced by a single intragastric intubation with ovalbumin in BDFl mice. Syngeneic lymphocyte transfers will be used to evaluate the time-course and localization of loss of responsiveness and appearance of suppressor T cells. Adherent-cell (macrophage) transfers will be used to assess the failure of oral immunization in this system, by comparisons of antigen uptake and presentation functions in macrophages from antigen-fed and parenterally primed mice. A possible role of digestion in antigen processing will be examined by testing the effects of in vitro peptic digestion products of ovalbumin upon specific responsiveness in normal mice. In contrast to traditional neonatal tolerance, mice are deficient in oral tolerance to ovalbumin at birth; lymphocyte transfers between adults and newborns will be used to identify the deficiency in newborn animals. Tolerance is assessed in terms of both reaginic (IgE) and total (ABC-33 antibody responses to parenteral test-immunization with specific antigen in adjuvant. This phenomenon may be of broad immunologic and physiologic significance, potentially reflecting an adaptive system for modulating specific immune responsiveness to frequently ingested environmental protein antigens.